AB0052 GENETIC EVIDENCE REVEALS CAUSAL LINK BETWEEN RHEUMATOID ARTHRITIS AND mTOR PROTEINS： A MENDELIAN RANDOMIZATION STUDY
Authors: Z. J. Yuan, R. Zhao, J. Y. Li, M. K. Yao, S. Y. Liu Yue, S. X. Zhang, X. Li, C. Wang
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Rheumatoid arthritis (RA) is a chronic autoimmune disease with hyperplasia of joint tissue and synovial inflammation1. And the mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase, which relates with cellular metabolism, promotes cell growth and inflammatory process2. Some studies show that some downstream proteins of mTOR are associated with RA, but having no directly genetic evidence. <h3>Objectives</h3> We conducted Mendelian randomization (MR) study to discover the genetically and statistically casual association between mTOR and RA. <h3>Methods</h3> A two-sample MR study was applied to investigate the association. Firstly, the GWAS data of 14 downstream proteins of mTOR, including plasma RP-S6K, EIF-4EBP2 and so on was obtain from the 3,301 European samples. And a summary statistic involved 14,361 cases and 43,923 controls was also acquired from the IEU OpenGWAS database. Meanwhile, we extracted Single-nucleotide polymorphisms (SNPs) which were related with mTOR (P &lt; 1.0×10-5) and satisfied the three assumptions for MR analysis as instrumental variables (IVs). Then, Inverse variance weighting (IVW), weighted median (WM), and MR-Egger regression were performed for MR statistical analysis by R Studio with packages “TwoSampleMR”. Additionally, MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) analysis was conducted to detect outlier instrument and remove pleiotropy. A leave-one-out analysis was conducted to avoid bias caused by a single SNP. <h3>Results</h3> Our study showed that no indication supporting the fact that the 14 downstream proteins of mTOR were causally associated with RA risk. The 15 SNPs of RP-S6K, 12 SNPs of EIF-4EBP2 and so on were selected as IVs for each 14 proteins. MR results showed that there was no causal relationship between RP-S6K and RA (OR = 1.03, CI: 0.89 - 1.20, P = 0.68). The results were same for EIF-4EBP2 (OR = 0.89, CI: 0.74 - 1.06, P = 0.18) and the other 12 proteins. No single SNP significantly biased the causal effect of mTOR and RA. No significant directional horizontal pleiotropy between each 14 downstream proteins and RA was presented. <h3>Conclusion</h3> Our study showed that a cause–effect connection did not appear to exist between mTOR proteins and RA, the findings of this study increased our understanding of the genetic associations, and may provide novel insights into the functional mechanism underlying the associations between SNPs and mTOR and RA. <h3>References</h3> [1]McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. <i>The New England journal of medicine</i> 2011;365(23):2205-19. doi: 10.1056/NEJMra1004965 [published Online First: 2011/12/14] [2]Li PP, Liu DD, Liu YJ, et al. BAFF/BAFF-R involved in antibodies production of rats with collagen-induced arthritis via PI3K-Akt-mTOR signaling and the regulation of paeoniflorin. <i>Journal of ethnopharmacology</i> 2012;141(1):290-300. doi: 10.1016/j.jep.2012.02.034 [published Online First: 2012/03/07] <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.